tbuckley/cabot-search huggingface dataset:
Abstract 14714: Marked Gradient Reduction Through a Transcoronary Alcohol Ablation of Septal Hypertrophy in a Patient With Cardiac Amyloidosis and Hypertrophic Cardiomyopathy
Authors: Daniel M Isaac, Karin Klingel, Ulf Landmesser, Bettina Heidecker
Journal: Circulation (2022)

A 66-year-old male with a history of carpal tunnel syndrome and hypertension presented with dyspnea (NYHA III), angina pectoris, and sinus bradycardia. On clinical examination, the patient was stable and euvolemic. A systolic murmur (III/VI) was audible in the 4th left intercostal space laterally, augmented after a Valsalva maneuver. An electrocardiogram revealed normal sinus rhythm, heart rate of 81 bpm, normal voltage, and non-specific ST-changes in I, II, III, aVF, V5, and V6. The patient underwent a transthoracic echocardiography, which revealed thickened ventricular walls (IVSd 23 mm, PWd 20 mm), hyperdynamic left ventricular ejection fraction (LVEF 75%), LVOT gradient of 150 mmHg maximum (after Valsalva maneuver), apical sparing on strain analysis, and a dilated atria. A coronary angiography ruled out coronary artery disease. A endomyocardial biopsy revealed hypertrophic cardiomyopathy combined with focal cardiac amyloidosis (Figure 1). Subtyping and genetic analysis revealed transthyretin (ATTR) wild-type amyloidosis. Accordingly, therapy with Tafamidis 61 mg daily was initiated. Given the relevant amount of hypertrophy depicted on the biopsy samples, the high LVOT gradient, and the patient’s debilitating symptoms despite maximal medical therapy, the decision was made to attempt a transcoronary alcohol ablation of the septal hypertrophy (TASH). The TASH reduced the LVOT gradient from 150 mmHg to 35 mmHg. After the procedure, the patient experienced significant symptom improvement (NYHA II) and was discharged the next day. This case illustrates the feasibility of marked LVOT gradient reduction in patients with amyloidosis and hypertrophic cardiomyopathy through a TASH procedure. Figure 1: Histology reveals hypertrophic cardiomyocytes and cardiac amyloidosis on Congo red staining.
Abstract 14946: Robust Genome Editing of Endothelial Hif-2α in Adult Mice by Ec-Targeted Nanoparticle Delivery of Prime Editing System Inhibits Pulmonary Hypertension
Authors: Yi Peng, Youyang Zhao, Daoyin Dong
Journal: Circulation (2022)

Introduction: Prime Editing (PE) is a site-specific mutagenesis approach for highly precise genome editing, thus has the potential for safer editing to treat human diseases. However, the genome editing efficiency has been shown only 5% in adult mice. The in vivo efficacy of prim editing remains unclear. Hypothesis: Endothelial cell-targeted nanoparticle delivery of the all-in-one plasmid DNA (15kb) expressing the prime editing under the control of CDH5 promoter will induce robust genome editing of Hif2a selectively in endothelial cells in adult mice and inhibit PH. Methods: To target endothelium for robust genome editing, we employed EndoNP1 nanoparticles to deliver the all-in-one prime editing plasmid DNA under the control of CDH5 promoter to adult WT and Egln1 Tie2Cre mice. The prime editing was designed to change 1-2 nucleotides to introduce a STOP codon in mouse Hif2a coding region. Hypoxia-induced PH in mice and Egln1 Tie2Cre mouse model of severe PAH were employed to determine the therapeutic potential of prime editing in PH treatment. Results: Single administration of mixture of nanoparticles and prime editing plasmid DNA caused 30% genome editing efficacy selectively in endothelial cells of WT mice and also Egln1 Tie2Cre mice. The genome editing efficiency was increased to approximately 50% with 2 administrations of the nanoparticle:plasmid DNA mixture in a 1 week interval, resulting in &gt;70% reduction of HIF-2a protein. One week after the 2 nd administration, WT mice were subjected to hypoxia (10%) for 3 weeks. Pulmonary hypertension was attenuated in the prime edited mice with endothelial Hif2a early stop codon. Conclusions: These findings for the first time demonstrate unprecedented efficacy of genome editing of prime editing selectively in ECs of adult mice which exhibit phenotype similar to genetic knockout mice. Thus, EC-targeted nanoparticle delivery of the prime editing system may have great potential for treatment of human diseases associated with endothelial cell dysfunction, such as pulmonary arterial hypertension.
Abstract 15146: A Flying Saucer- Asymptomatic Migration of an Atrial Septal Defect Occluder Device to the Aortic Arch - No Good Deed Goes Unpunished!
Authors: Amro Aglan, Rohan Parikh, michael cundiff, Sourbha Dani
Journal: Circulation (2022)

Introduction: Though safe, the transcatheter closure with an atrial septal defect for secundum atrial septal defect (ASD) is associated with complications, such as device dislodgement. Case report: A 51-year-old female with a complex fenestrated secundum ASD (16mm superior defect and 14mm inferior defect with insufficient aortic rim) with hemodynamically significant shunt causing right heart dysfunction underwent placement of two atrial septal defect occluder devices (Amplatzer). While there was no shunting noted on immediate post-procedure transthoracic echocardiogram (TTE), a follow-up TTE after a year showed residual left to right shunting across the ASD. Transesophageal echocardiogram (TEE) showed a single occluder device (inferior) in place and a second device (superior) lodged in the distal aortic arch at the level of the left common carotid and left subclavian artery with mild local flow acceleration (aortic velocity 2.6 ms/s) and no superimposed device thrombus. Her only complaint was recurrent headaches, which pre-dated the procedure and were attributed to ocular migraine by her neurologist. The patient underwent a transcatheter procedure to attempt the retrieval of the dislodged device. The proximal end of the device was found adherent to the aortic wall. Aortogram revealed excellent flow around the device. The procedure was aborted due to the risk of dissection. Since the device did not cause any adverse effects and would likely continue to endothelialization. Conclusion: Atrial septal occluder device dislodgement can occur several months after implantation. Careful monitoring is required particularly when the ASD rim is insufficient. In cases of migration and adherence to the aortic wall without hemodynamic consequences, the device can likely be safely left in place to endothelialize. Despite a faster recovery with percutaneous procedures, a surgical approach should be considered in younger patients to avoid such complications.
Abstract 15093: Elevated Risk of Recurrent Ablation in Black Compared to White Patients With Atrial Fibrillation: Another Paradox of Atrial Fibrillation in Blacks
Authors: Juzer Ali Asgar, Sanchit Duhan, Parshotam Kundan, Naval Walia, DANIELLE KRAFT, Kevin Bliden, Udaya Tantry, Paresh Shah, Paul Gurbel, Mohammed Kanjwal
Journal: Circulation (2022)

Introduction: Lower prevalence of atrial fibrillation (AF) despite a higher prevalence of risk factors in blacks compared to whites (AF paradox) has been reported. However, less information is available about recurrent ablation events in blacks compared to whites. Methods: Demographic characteristics and one-year recurrent ablation events were analyzed in AF patients admitted to a community hospital from 2018 to 2021. Results: Recurrent AF ablation occurred in 3.7% (16/435) of the study population and was significantly higher in black compared to white patients [9/86 (10.5%) vs. 7/349 (2.0%), respectively, p=0.0001]. Black race and history of atrial flutter were predictors of recurrent AF ablation (p&lt;0.05) within one year of initial ablation. Black patients were younger (p=0.03) with a significantly higher prevalence of hypertension, diabetes, cardiomyopathy/heart failure, thyroid disease, renal disease, sleep apnea, COVID-19, pacemaker/AICD placement, and history of Ventricular tachycardia (Table). Concomitant medications were similar between races besides higher use of antihypertensive medications in black patients (Table). Conclusions: In our community hospital setup, black patients with AF had a higher prevalence of comorbidities and significantly higher incidence of one-year recurrent ablation events despite similar therapy compared to white patients. These observations should be explored in a larger prospective study to understand the differential association of comorbidities in black AF patients and associated higher risk for recurrent events.
Abstract 15153: Inhibition of the Tumor Suppressor Wwox Expression Alters Mitochondrial Dynamics in PASMC
Authors: Marta T Gomes, Rafael Polidoro, Yang Bai, Roberto F Machado
Journal: Circulation (2022)

Introduction: Pulmonary arterial hypertension (PAH) contributes to the morbidity and mortality of several patients with different pulmonary and cardiac diseases. Among other factors, the pathogenesis of PAH involves exaggerated pulmonary artery smoot muscle cell (PASMC) hyperproliferation, resistance to apoptosis and energy metabolism shift associated with alterations in mitochondrial metabolism and dynamics. The WW domain-containing oxidoreductase gene ( WWOX ) is a tumor suppressor gene that has the ability to interact with a large number of proteins, exerting its activity through a wide variety of molecular actions in specific cells. WWOX loss affects cell proliferation, motility, and deregulates expression of genes involved in cell cycle regulation, metabolism, and DNA damage in a variety of cancers. Considering that a similar phenotype is observed in cancer cells and PAH, we sought to investigate whether the loss of WWOX in PASMC is associated abnormalities of mitochondrial metabolism and dynamics in PAH. Methods and Results: In PASMC, inhibition of WWOX expression by short-interfering RNA (siRNA) decreased oxygen consumption by 30% when compared with siRNA control. Dysregulation of mitochondrial bioenergetics in WWOX-silenced PASMC was attributed to modulation of the oxidative state of mitochondrial electron transport chain proteins, showing that succinate dehydrogenase (SDH)(complex II) expression decreased by 15% in relation to siRNA control. JC-1 and mitotraker red CMXROS staining demonstrated that WWOX- silenced PASMC had hyperpolarized and fragmented mitochondria that generated more reactive oxygen species than the control. Changes in mitochondrial dynamics were detected with increased phosphorylation levels of the fission protein, dynamin-related protein 1 (DRP-1) and, decreased Mitofusin 2 and 1 protein levels, positive regulators of mitochondrial fusion. Conclusion: Loss of WWOX expression causes changes in PASMC mitochondrial metabolism and dynamics stimulating these cells to use different resources as a way to reprogram their metabolism and ensure their survival. These alterations may contribute, for example, to the stimulation of vascular remodeling, which consequently promote the pathogenesis of PAH.
Abstract 15103: Stratifying Coronary Artery Disease (CAD) GWAS Loci Using Cardiac Perfusion Positron Emission Tomography to Identify Loci for Coronary Microvascular Disease
Authors: Shefali Verma, Lindsay Guare, Brett Irving, Michael Levin, Marie A Guerraty
Journal: Circulation (2022)

Introduction: Coronary Microvascular Disease (CMVD), defined as disease of the coronary pre-arterioles, arterioles, and capillaries, accounts for 30-50% of the burden of Ischemic Heart Disease (IHD). CAD GWAS studies have identified more than 235 loci, however, the populations enrolled represent heterogeneous IHD with inclusion criteria that include ischemia without confirmation of obstructive CAD (Ischemia with non-obstructed Coronary Arteries). Hypothesis: We hypothesize that CAD GWAS studies are really IHD GWAS studies and a subset of patients enrolled have CMVD as the etiology of their ischemia. Thus several CAD GWAS loci may be CMVD loci. Here we use quantitative measures of myocardial blood flow (MBF) and MBF reserve (MBFR) from cardiac Perfusion PET studies to stratify known CAD loci for CMVD. Methods: We performed a genomic association study for 235 known CAD loci in 383 samples of European (EUR) and 539 samples of African ancestry (AFR) in the Penn Medicine Biobank using clinical Rubidium-82 PET using REGENIE software. Models were adjusted for age, sex, age 2 , age x sex, 5 principal components, and batch corresponding to phenotype extraction. We examined regions within 250kb of known CAD loci for association with PET-derived MBF and MBFR. Bonferroni corrected P-value &lt; 2.13e-4 was considered significant. Results: We found 40 loci in patients of AFR ancestry and 11 CAD loci in patients of EUR ancestry that were significantly associated with MBFR, including several genes which are known to play a role in microvasculature function and angiogenesis (VEGFa, FLT1, and FGF1). Stress MBF values have been shown to reflect epicardial CAD. We found 28 loci in patients of AFR ancestry and 12 loci in patients of EUR ancestry which were significantly associated with stress MBF and are mostly distinct from loci associated with MBFR. One notable exception is PRDM16 which was highly significant in both phenotypes. Conclusions: Our study sub-stratified variants previously associated with CAD to identify those that may be involved in CMVD. Several genes known to be involved in microvasculature function (VEGFa, FLT1, and FGF1) were putative CMVD genes. PRDM16 was associated with stress MBF and MBFR. This work prioritizes CAD loci for further study of mechanisms of CMVD.
Abstract 14625: Strategies for Maturation of Cardiovascular Organoids for Modeling Acquired and Inherited Adult-Onset Cardiomyopathies
Authors: Noam Kazma, Idan Haiim, Caroline Bashai, Anastasia Nevo, Yaara Libai, Oren Caspi
Journal: Circulation (2022)

The development of Induced Pluripotent Stem cells (iPSC) technology has provided a lot of opportunities for disease modeling and cardiovascular regeneration. Two leading limitations of most iPSC-based modeling systems are: the relatively immature phenotype of the generated cardiomyocytes (CMs) (which exhibit fetal-like characteristics and fail to fully emulate the physiology processes of adult myocardium); and the lack of multicellularity (supporting cells such as endothelial cells, cardiac fibroblasts, and smooth muscle cells) facilitating the function of the organoid as an authentic cardiac tissue.The current project aims at engineering mature cardiovascular organoids for modeling acquired and inherited cardiomyopathies left ventricular hypertrophy and inherited hypertrophic cardiomyopathy. The expression of cardiac Troponin I (TnI) isoform 3 is the hallmark of sarcomere maturation.The study planned will be conducted using an iPSC tissue culture system. Cell and tissue maturation was evaluated at the morphological level by confocal microscopy, at the molecular level by RT-qPCR and western blot analysis, and at the functional level by force generation and calcium imaging. Engineered cardiovascular organoids are evaluated by a tailor-made high-throughput robotic system allowing to measure electrophysiological signals. Initial Results: CMs maturation inducing strategies have been implicated by combining metabolic maturation together with factors associated with robust maturation (mTOR inhibitor, hormonal supplements, and steroids). The strategy used resulted in significant maturation as evaluated by molecular markers (significant induction of TNNI3 levels) and physiological ones (shorter contraction duration, relaxation time, and time-to-peak). In addition, protocols for simultaneous maturation of CMs together with endothelial cells, cardiac fibroblasts, and smooth muscle cells have been developed.The project suggested providing a unique opportunity to establish cardiovascular organoid-based platforms for modeling acquired and inherited adult-onset cardiomyopathies. The platform may be used for gaining mechanistic insights, toxicity screening, and target identification as well as drug discovery.
Abstract 15085: Modest Reduction in Ankle-Brachial Index Measurements and Risk of Major Adverse Limb Events Among 133,373 Veterans
Authors: Aaron W Aday, Svetlana K Eden, Charles W Alcorn, Hilary A Tindle, Joshua A Beckman, Matthew S Freiberg
Journal: Circulation (2022)

Introduction: Low resting ankle-brachial index (ABI) serves as a non-invasive biomarker of poor limb outcomes. Whether modest decrements in ABI translate into higher risks of major adverse limb events (MALE) are unclear, particularly among women and minorities, because prior studies are small or lack racial diversity and incident outcomes. Methods: We analyzed data from participants in the Veterans Affairs Birth Cohort, a prospective, longitudinal cohort of veterans born between 1945-1965 with no clinical history of PAD prior to ABI testing. Participants were enrolled on or after 1/1/2000 and followed through 12/31/2016. The exposure was resting ABI and the outcome was MALE defined as limb revascularization or amputation based on VA and Medicare ICD-9/10 and CPT codes. Cox proportional hazards models assessed the association between ABI and MALE among black and white men and women. Models were adjusted for demographics and PAD risk factors ( Figure Legend ). Results: The analysis included 23,733 black men, 1,257 black women, 96,220 white men, and 2,813 white women. There were 14,431 MALE events. Risk for MALE across the ABI spectrum followed a j-shaped distribution ( Figure ). Both low and high ABIs were associated with an increased risk of MALE for black and white men and women ( Figure ). When we analyzed each sex/race group separately, as compared to a normal ABI measurement (1.11-1.20), a modestly reduced ABI (0.81-0.90) was associated with a significantly increased risk of MALE: black men HR adj , 2.17; 95% CI, 1.67-2.80; black women HR adj , 3,24; 95% CI, 1.21-8.69; white men HR adj , 3.04; 95% CI, 2.68-3.46; white women HR adj , 4.56; 95% CI, 1.73-11.99. Conclusions: In a large, diverse cohort of people free of prior PAD, a modest reduction in ABI was associated with a greater than two-fold increased risk of MALE for all sex/race groups. Further studies are needed to better understand why MALE occurs in this patient population despite only mildly reduced limb perfusion.
Abstract 15399: Proteomic Landscape of Plasma Lipoprotein Responses to Regular Exercise
Authors: Jacob L Barber, Guoshuai Cai, Jeremy M Robbins, Prashant Rao, Michael Mi, Sujoy Ghosh, Clary Clish, Daniel H Katz, Claude Bouchard, Robert E Gerszten, Mark A Sarzynski
Journal: Circulation (2022)

Introduction: Lipoproteins are among the strongest predictors of CVD and are altered through regular exercise. However, the molecular changes underlying the potential benefits of exercise on plasma lipoproteins are unclear. Methods: Proteins (n=4979) were quantified from the plasma of 647 Black and White adults (56% women, mean age = 34.9 yrs) before and after 20-weeks of endurance exercise training using SomaScan. All subjects had complete data for 7 lipoprotein traits that improved with training: HDL-C, TG, large TG rich lipoprotein particles (LTRLP), small LDL particles (SLDLP), large HDL particles (LHDLP), TRLP size, and LDLP size. Fully adjusted linear mixed models were used to test the association of 1) baseline proteins with baseline lipoproteins and 2) delta proteins with delta lipoproteins (delta = post training - baseline value). Significance was determined as FDR&lt;0.05. Results: We identified numerous proteins associated with baseline levels of at least one of the seven lipoprotein traits (range: 48-1099) and whose changes in response to regular exercise were associated with concomitant changes in lipoproteins (range: 4-95) ( Table 1 ). Substantial overlap was found between proteins associated with lipoproteins across timepoints, with 16 proteins associated with 4 or more lipoprotein traits at both timepoints. Plasma abundance of 12/16 proteins significantly changed with training (FDR &lt;0.05). Additionally, for these proteins plasma abundance changed in concordance with the beneficial direction of the associated lipoprotein trait (e.g., proteins associated with atheroprotective lipoprotein traits increased with training and proteins associated with atherogenic traits decreased). Conclusions: Beneficial alterations to plasma lipoproteins with regular exercise are reflected in changes to the plasma proteome. Proteins identified here may represent novel markers of the benefits of regular exercise and of systemic lipoprotein metabolism.
Abstract 15210: Association of Circulating Biomarkers With Progressive Left Ventricular Remodeling and Hypertrophy in Patients With Aortic Stenosis: Results From the Progressa Study
Authors: Kathia Abdoun, Lionel Tastet, Mylene Shen, Romain Capoulade, Marie-Ange Fleury, Marie Arsenault, Elisabeth Bédard, Philippe Pibarot
Journal: Circulation (2022)

Introduction: Aortic stenosis (AS) is associated with progressive left ventricular (LV) remodeling and hypertrophy, ultimately leading to cardiac decompensation. Measurement of circulating biomarkers may be useful to identify AS patients with higher risk of maladaptive LV remodeling, a potent marker of the transition to heart failure. We hypothesized that multiple circulating biomarkers are associated with faster progression of LV hypertrophy in patients with AS. Methods: One hundred and forty-six asymptomatic AS patients (66±13years, 75% male) prospectively enrolled in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent Doppler-echocardiography to measure AS severity, LV mass indexed to body surface area (LVMi) and LV relative wall thickness (RWT). The annualized changes in LVMi and RWT were calculated between baseline and last follow-up visit (mean follow-up of 2.5±1.88 years). Results: At baseline, 16% of patients had mild (i.e. peak aortic jet velocity [Vpeak] 2.0-2.9 m/s),76% moderate (Vpeak 3.0-3.9 m/s), and 8% severe (Vpeak ≥4.0 m/s) AS, mean LVMi and RWT were 106±23 g/m 2 and 0.47±0.07 respectively. Among biomarkers, baseline level of triglycerides, D-dimer and tumor antigen 125(Ca-125) were significantly associated with LVMi progression rate (β:0.16,p≤0.05), (β:0.18,p≤0.05) and(β:-0.20,p≤0.05) respectively. Soluble (ST2) protein and alkaline phosphatase (ALP) were the only factors independently associated with the annualized change in RWT. In multivariate analysis adjusted for age, gender, comorbidities, AS severity, cardiac biomarkers; triglycerides and D-dimers remained significantly associated with faster progression rate of LVMi (all, p≤0.05), while lower level of CA125 remained significantly associated with LVMi annualized change (β=-0.21, p=0.01). After similar multivariate adjustment, higher levels of ST2 and ALP remained significantly associated with faster progression rate of RWT (all, p≤0.05). Conclusion: Several blood biomarkers were independently associated with faster progression of LV remodeling and hypertrophy in patients with AS. A multiple biomarker approach may be useful to assess LV health and predict the risk of early phases of heart failure in AS.